If only the story of obesity were exclusively composed of characters from the worlds of diet, exercise, and chemical exposures. Unfortunately, it is more complicated than that. As I have been hinting at all along, there are other factors that influence whether you are overweight or obese, independent of the energy balance equation. In this chapter, we will talk about seven important, interrelated factors, all of which interact with diet, exercise, and obesogens. They include the following:

Your microbiome

Consumption of sugar, including artificial sweeteners

The quality of your sleep

Your levels of stress

Pharmaceutical drugs you take

Exposure to certain viruses

Inherited “fat” genes

Note that entire books could be written about each of these topics, so here I will summarize and highlight the essentials as they relate to your weight. Some of these topics may not seem directly related to obesogens, but they are. It is important for you to look at the impact of obesogens as a whole life problem—it is not a matter of just buying organic foods and seeking BPA-free bottles. By the same token, you cannot simply improve the quality of your sleep and exercise more to lose weight. To achieve permanent weight loss, you must evaluate your entire lifestyle and identify your personal vulnerabilities. Let’s take each of these seven factors into consideration, starting with the friendly microbes that inhabit your body right now and have a say in everything about your weight equation.

MEET YOUR MICROBIOME

If you grew up in the twentieth century, then you probably came to understand microbes as small organisms invisible to the naked eye that can cause diseases in humans. Tuberculosis, bubonic plague, and whooping cough, for example, are all caused by microbes, specifically bacteria. You have no doubt heard about methicillin-resistant Staphylococcus aureus (MRSA) and necrotizing fasciitis (flesh-eating bacteria). Prior to the development of antibiotics, infectious diseases carried by bacteria were a major cause of death.

Only recently—in the twenty-first century—have we recognized that many microorganisms are, in fact, important for our health and vitality. The colonies of microbes, known collectively as the “microbiome,” that inhabit our bodies—inside and out—and may outnumber our own cells by three-to ten-fold have stolen the spotlight lately. The human microbiome weighs about three pounds, the same as our liver or brain. The microbiome has become an important emerging new field of study since the pioneering work of Dr. Jeffrey Gordon at Washington University in St. Louis showed that the gut microbiome has profound impacts on our physiology and metabolism.¹²⁴^,¹²⁵ The microbiome comprises more than one hundred trillion single-celled microbes, mostly bacteria, that ride around with us on our skin and in our mouths, noses, intestines, and genitalia. The gut microbiome synthesizes vitamins, helps us digest food, bolsters our immune systems, and even boosts our brain function. Perhaps you will not be surprised to learn that a variety of lifestyle factors may play an important role in the composition of our microbiome and, hence, our health and well-being. Studies are currently under way to understand this complex relationship, but such factors may include the type of diet we eat (carbohydrate vs. fat, meat eaters vs. vegetarians, sugar vs. artificial sweeteners), how much we exercise, levels of stress, and what types of chemicals we are exposed to.¹²⁶

Many microbiome projects are under way around the world that employ state-of-the-art genomic methodology to better understand how bacterial symbionts^viii influence our physiology.¹²⁷ Large gaps in our knowledge about the interactions among diet, lifestyle, gut microbes, and health still exist, but by some measures, these collective projects may become more significant and game-changing in medicine than the human genome project. The gut has a separate nervous system, the so-called enteric nervous system, that integrates information about the state of the gastrointestinal tract to modulate how it functions. The enteric nervous system is strongly influenced by small molecules produced by gut bacteria, which means that they can have profound effects on what we eat and how we feel and behave.

The microbiome is a subject deserving of its own book(s), especially with respect to how it affects health and disease, from autoimmune disorders to cancers. For the purposes of our discussion, I will focus chiefly on how the microbiome impacts weight and obesity. Recent research has uncovered some stunning new clues to improve the weight loss endeavor, showing us that being overweight or obese may have more to do with the microbial profile in your gut than with your willpower to eat less and exercise more, or even your personal genetics. By changing the way we store fat, impacting how we balance levels of glucose in the blood, influencing the expression of genes that relate to metabolism, and affecting how we respond to hormones that make us feel hungry or full, our gut bacteria can have important influences on whether we lose or gain weight and how easy this is to accomplish.

Put another way, the actions of the microbiome further dismantle the “calories in versus calories out” equation when it comes to weight, because the microbiome plays a fundamental role in energy balance. The types of bacteria in our gut determine how much energy we extract from food as it passes through the gastrointestinal tract—that is, how much of the potential energy in food we consume is actually taken in and used. Animal studies show that if the microbiome has too many types of bacteria that efficiently harvest calories from food, more of the calories eaten will be absorbed, which can lead to increased body fat and, eventually, obesity. It is likely, although not yet proven, that the same occurs in humans.

In many cases, when a baby moves through the birth canal, it is “showered” by microbes that begin to colonize its gastrointestinal tract. Although there may be some exposure to microbes in the uterus via the placenta, the vast majority of the earliest colonizers come from the birth process. Those of us born via the much more sterile cesarean section tend to have different microbial profiles from those who are born naturally. It is not known yet whether the birth process itself compared with cesarean section alters the microbial populations so these differences are only an association.

Recent studies show that babies who are not exposed to a rich array of beneficial bacteria in early life will live with a higher risk for obesity and diabetes than their peers who develop healthier microbiomes.¹²⁸^,¹²⁹ The same holds true for babies who are exclusively formula fed, because they miss out on the healthy dose of protective antibodies and beneficial bacteria provided by breast milk and mom’s skin. Early evidence of gut bacteria relating to obesity came from animal and human studies comparing intestinal bacteria in obese and lean subjects. The intestinal microbiomes of slender people appear to be much different from those of obese individuals. Peter Turnbaugh, Jeffrey Gordon, and colleagues convincingly showed that the microbiome was closely linked with obesity.¹³⁰ They started with genetically identical mice whose intestines completely lacked bacteria—so called germ-free (gnotobiotic) mice. Then they transplanted microbes from the intestines of obese or lean mice into the guts of these gnotobiotic mice. They found that the gnotobiotic mice adopted the obesity phenotype of the donor transplant—that is, the obese microbiome made the host mice fatter, whereas the lean microbiome kept the hosts lean, irrespective of diet.¹³⁰ Gordon and colleagues did similar experiments transplanting the microbiome from obese people or lean people into gnotobiotic mice and again found that the obese microbiome made the host mice fatter. The number and types of microbes in the obese vs. lean microbiomes were also different, with the obese microbiome much less diverse.

If this is not enough to convince you, they did a further experiment in which the microbiomes from obese vs. lean twin sisters were transplanted into germ-free mice.¹³¹ As in the previous experiment, the mice receiving the lean microbiome stayed lean and those receiving the obese microbiome became about 15 percent fatter, despite eating the same diet. Remarkably, when the two types of mice were housed together in the same cages, the microbiome from the lean mice was transferred to the mice that had previously received the obese microbiome, preventing the latter from becoming fatter. This shows that the microbiome trumped both diet and genetics in controlling the fat content of these mice.

We also know that certain types of fats can affect the composition of the gut bacteria, which then influences whether an animal develops obesity-related inflammation. In 2015, a study published in Cell Metabolism showed that mice fed a high-fat diet composed mostly of lard for eleven weeks developed signs of metabolic disease, while mice that ate the same amount of calories from fat, but as fish oil, remained healthy.¹³² When the researchers transplanted gut bacteria from fish-oil-fed mice to gnotobiotic mice and then subsequently fed the animals lard, the mice were protected from the usual unhealthy effects of the saturated fat. Previous studies had provided circumstantial evidence connecting the composition of the gut microbiome with food cravings produced by the hunger center of the brain.¹³³ This study, led by scientists at the University of Gothenburg in Sweden, went much further by revealing that feeding different types of fat resulted in very different gut microbiome profiles.¹³²

Where the science really shines a light on the power of the microbiome is when we consider the effects of gastric bypass surgery on not just weight loss, but the almost overnight reversal of type 2 diabetes. Gastric bypass procedures involve making the stomach and small intestine smaller. Initially, it was thought that the rapid weight loss typically seen in patients who underwent the surgery was attributed to the individual eating less. But we now have evidence that a major portion of the weight loss is due to changes in the gut bacteria—changes that happen in response to the anatomical adjustments made by the surgery. It is unclear whether this results from dietary shifts that favor the growth of different bacteria or some other cause.¹³⁴^,¹³⁵

Considering all of these studies together, it is clear that the quality and diversity of the gut bacteria factor mightily into metabolism and weight in animal studies and likely in humans as well, although the jury is still out. Explaining all the factors that contribute to the biochemistry and physiology of the microbiome and how these interact with physiology would take an entire book; plus, the story is far from complete. We will focus on two particular examples that illustrate the point: natural and artificial sweeteners—two related dietary villains that further demonstrate the importance of a healthy gut microbiome.

THE ROLE OF FRUCTOSE, SUGAR, AND ARTIFICIAL SWEETENERS

As mentioned earlier, fructose—a sugar naturally found in fruit and honey—has become one of the most common sources of calories in the U.S. (and increasingly the Western) diet. The most common sugar in nature, sucrose, is a disaccharide—one molecule of fructose chemically linked to one molecule of glucose. But the majority of the fructose we consume is not in its natural form (that is, as part of sucrose) or source (whole fruit). The average U.S. citizen consumes 163 grams of refined sugars (652 calories) per day, and of this, roughly 76 grams (302 calories) are from a highly processed form of fructose, derived from high-fructose corn syrup (HFCS).¹³⁶ Professor Robert Lustig from the University of California–San Francisco has been sounding the alarm about sugars, particularly added, processed fructose, for many years now, as detailed in numerous scientific publications and his book Fat Chance.¹³⁷ Other experts, such as Dr. Michael Goran, director of the Childhood Obesity Research Center (CORC) and professor of preventive medicine at the University of Southern California, have argued that the amount of fructose we consume could be considerably higher given the murkiness, if not downright inaccuracies, in sugar labeling. Dr. Goran and his colleagues have discovered that the HFCS used in several popular beverages is delivering a level of fructose much higher than commonly thought. Although the manufacturers claim that sodas and beverages were made with HFCS 55 (55 percent of the sugar as fructose and 45 percent as glucose), Goran and his colleagues identified levels of free fructose as high as 65 percent in soda purchased around the Los Angeles area.¹³⁸ These results were published in the journal Obesity in 2011. Not surprisingly, the beverage industry responded by sponsoring studies showing that the HFCS 55 they tested contained close to 55 percent fructose.

Goran countered with a follow-up study in the journal Nutrition in 2014 where he commissioned three independent labs to measure fructose levels in a variety of beverages by different methods.⁵³ These studies confirmed the initial findings. Goran’s team collected and analyzed the composition of thirty-four popular drinks and found that those made with HFCS contained 50 percent more fructose than glucose and that some product labels misrepresented the fructose content. For example, they found that while the label on Pepsi Throwback indicated it is made with real sugar (sucrose), in reality it contained more than 50 percent fructose. Sierra Mist, Gatorade, and Mexican Coca-Cola also were shown to have higher concentrations of fructose than reported by their labels. You can believe whom you choose, but I know Michael well and think that his studies are quite convincing.

Now, you might be wondering why the amount of fructose is such a big deal and thinking that 55 percent is not so different from 50 percent. Sugar is just sugar, after all, right? That is what the commercials for HFCS say. But HFCS is not the same as sucrose or the fructose that occurs in nature. In fact, many scientists have suggested that increased consumption of sugars in general, and fructose in particular, is contributing to the obesity epidemic; that fructose is a major factor in creating a so-called Westernized gut microbiome that lacks diversity and extracts more calories from food, essentially feeding your fat cells with a “thrifty metabolism.”¹³⁹ We consume more HFCS per capita than any other nation,¹³⁶ and consumption has doubled over the last three decades as public health experts have urged us to cut fat consumption. Over the same time period, the incidence of type 2 diabetes has tripled. For these reasons alone, many experts make a connection between the increased diabetes (and obesity) and consumption of sodas, sports drinks, and energy drinks. Numerous studies now show that consuming fructose is associated with impaired glucose tolerance, insulin resistance, high triglycerides, and hypertension. As Goran wrote in a letter to former first lady Michelle Obama, “Although common table sugar (sucrose) is also comprised of glucose and fructose, nature balances them in equal proportions, and joins them by a bond for which the human body produces an enzyme (sucrase) to break down before absorption into the bloodstream. Therefore, the body absorbs fructose from sucrose more slowly than fructose from HFCS.”¹⁴⁰ Natural fructose is found in fruits and vegetables together with dietary fiber. The absorption of this fructose into the bloodstream is blunted by this fiber. In contrast, high-fructose corn syrup contains free fructose, which disrupts liver metabolism and, along with excess glucose, elevates blood sugar levels and exhausts our pancreas.

Fructose is particularly troublesome in the body because it is primarily metabolized and stored in the liver, where it stimulates fat storage. Fructose also increases triglyceride levels in the blood and does not spike blood glucose or stimulate insulin production as does glucose. In turn, this means that your body does not produce leptin in response to fructose ingestion, so the body does not sense satiety, which can lead to increased food consumption. This same outcome—the lack of satiety upon consuming fructose—is also seen with artificial sweeteners. The human body cannot digest artificial sweeteners, which is why they have no calories. But the sensation of sweetness itself triggers some of the same biological responses as does sugar consumption, and the artificial sweeteners still must pass through our gastrointestinal tract.

For a long time we assumed that artificial sweeteners were, for the most part, inert ingredients in terms of affecting our physiology. Although it was first shown in 1988 that cyclamates, a class of artificial sweeteners, could modify how the microbiome behaved,¹⁴¹ it was generally assumed that sugar substitutes such as saccharin, sucralose, and aspartame did not have a metabolic impact because they do not raise blood glucose levels. But it turns out that they can indeed wreak havoc (and cause the same metabolic disorders as real sugar) by triggering transient elevations in insulin levels (which increases fat storage) and alter the microbiome in ways that favor unhealthy biology. Studies are emerging to demonstrate that the gut bacteria of people who regularly consume artificial sweeteners is very different from those of people who do not. Consumption of artificial sweeteners has been linked with increased weight, higher fasting blood glucose, and elevated risk for developing type 2 diabetes. In 2013, French researchers published the results of a study that followed more than sixty-six thousand women since 1993: they found that the risk for developing type 2 diabetes was more than double for those who drank artificially sweetened drinks as compared with women who consumed sugar-sweetened beverages.¹⁴² A recent meta-analysis ^ix of more than thirty studies, including more than four hundred thousand participants evaluated over ten years, revealed no benefit of artificial sweeteners for weight loss and found that long-term use of such sweeteners might be associated with increased BMI and risk for cardiometabolic conditions.¹⁴³ Clearly more research in this area is needed.

This discovery of a link between artificial sweeteners and the state of the gut microbiome stunned the scientific community when it landed in the journal Nature in 2014.¹⁴⁴ Eran Segal and Eran Elinav at the Weizmann Institute of Science in Israel, whom we met in chapter 1, led their team on a series of experiments to answer one question: Do artificial sweeteners affect healthy gut bacteria? Segal, Elinav, and their colleagues started by adding the fake sugars—saccharin, sucralose, or aspartame—to the drinking water of different groups of mice. They gave other groups of mice the natural sugars glucose or sucrose in their water; the control group drank plain, unsweetened water. Eleven weeks later, mice that drank the artificial sweeteners exhibited signs of glucose intolerance compared with the controls. In other words, they could not control their blood glucose levels very well. This was an important finding, but where the rubber met the road in this experiment was when they tested the effects of artificial sweeteners on the microbiome.

To determine whether gut bacteria had anything to do with the link between drinking fake sugar and developing glucose intolerance, these researchers gave the mice high doses of antibiotics for four weeks to essentially eliminate all bacteria in their gut. Surprisingly, after a nearly complete elimination of their gut microbiomes, all of the groups were able to metabolize sugar equally well. As a final test of how fake sugars affect the microbiome, the researchers transplanted gut bacteria from mice that had consumed saccharin into gnotobiotic mice with no gut bacteria of their own. Within just six days, the now tainted mice had lost some of their ability to process sugar. Genetic analyses of the gut microbiome told the story: the saccharin microbiome was considerably different from the pretreatment microbiome. Some types of bacteria became more abundant, while others diminished, reminiscent of what Gordon and colleagues found for obese vs. lean microbiomes.¹⁴⁴ No doubt you are wondering whether this also occurs with your favorite artificial sweeteners in humans. These studies are under way but I will not be surprised if the results show that fake sugar has been faking us out for a long time.

Although we don’t yet have any definitive studies to show the impact of environmental chemical obesogens on the microbiome, our preliminary studies, show that tributyltin, which we learned about in chapter 2, alters both the microbiomes and the metabolomes (the set of small chemicals produced as a result of ongoing metabolic processes in the body) of treated animals and their descendants. These studies in my lab and elsewhere are just beginning; future research will likely reveal which obesogens assault the health and functionality of the gut microbiome and how this in turn impacts healthy human physiology and metabolism. In the future, we should also be able to learn what we can do to preserve optimal intestinal ecology, from dietary strategies to the use of supplements such as prebiotics and probiotics. I would be careful about jumping onto this bandwagon right now, though. We simply do not know enough yet to reliably predict which bacteria in what balance promote optimum health. One thing we recognize can make us unhealthy and overweight is poor sleep. The research in this area—sleep medicine—is now extensive.

SOUND SLEEP PROMOTES A HEALTHY CIRCADIAN CLOCK

We all know people who claim to consistently get by on four or five hours of sleep. Indeed, after I presented our work at a symposium on nutrition, my colleague Dr. Francisco Ayala (one of the giants in genetics) noted that he had trained himself as a graduate student to function well on five hours of sleep a night so that he could outwork other researchers. Francisco is rail thin and wondered why, if sleep was so important, he was not fat. The answer: Who knows? Kudos to those who can get by on little sleep without this affecting their metabolism and overall risk for certain health challenges (not to mention feeling good and energetic). But for the great majority of us, sleep is more vital than we imagine, and most of us need a good seven to nine hours nightly. I average around seven a night myself, though sometimes I could use a little more.

Sleeping fewer than seven to eight hours in a twenty-four-hour period, or experiencing irregular sleep sessions during which there is inadequate time spent in deep, restorative sleep, has been shown to be associated with a spectrum of health challenges, from cardiovascular disease, high blood pressure, and diabetes to unintentional accidents, learning and memory problems, depression and other mood disorders, weight gain and obesity, and an increased risk of dementia, including Alzheimer’s disease, cancer, and premature death. Dr. Matthew Walker, a professor of neuroscience and psychology at the University of California–Berkeley, used to say that sleep is the third pillar of good health, alongside diet and exercise. But given his research into the impact of sleep on the brain and nervous system, he now teaches that sleep is the single most effective thing we can do to reset our brains and bodies, as well as increase a healthy life span.¹⁵⁰^,¹⁵¹ Several recent studies have revealed a possible mechanism for why this is so.

In 2012, Dr. Maiken Nedergaard and her colleagues at the University of Rochester showed that cerebrospinal fluid flow through the brain increased dramatically when mice were sleeping, but not when they were awake.¹⁵² Cerebrospinal fluid is found in the brain and spinal cord, where it bathes and protects the central nervous system and eliminates waste products. They hypothesized that this flow might function like the lymphatic system in the body, draining tissues of cellular breakdown products and waste for eventual disposal. They named this the “glymphatic” system. In a follow-up study, they found that, in fact, this cerebrospinal fluid flow cleared toxins from the brain.¹⁵³ This has profound implications for our understanding of sleep—you must sleep in order for your brain to be cleared of waste products so that it can function properly.¹⁵⁴

As with the parallel patterns of increased sugar consumption correlating with an increase in obesity, there has been a similar pattern in the increase in sleep deprivation and obesity. On average, Americans sleep about two fewer hours each night than they did a century ago. And only 15 to 30 percent of teenagers get the eight and a half hours a night recommended for them. It can be hard to appreciate the value of sleep, and for a long time we didn’t really understand its purpose. Every animal sleeps, though, so there must be a logical, non-negotiable reason. In addition to its role in clearing the brain of toxins, sleep has a commanding role in our hormonal cycles, which in turn affect our basic physiology down to the speed and efficiency of our metabolism.

Every living organism has internal biological clocks called circadian rhythms. We have clocks in every cell in our body—a clock in our heart, muscles, liver, pancreas, and so on. These clocks regulate patterns of repeated activity associated with the environmental cycles of light and dark or day and night. These are rhythms that repeat roughly every twenty-four hours, and they include our sleep-wake cycle, the ebb and flow of hormones, and the rise and fall of body temperature that correlate with the twenty-four-hour solar day. They dominate all metabolism and physiology in most life forms, in fact. When your circadian rhythm is not synchronized properly with the twenty-four-hour solar day, you will not feel 100 percent. Most of you have experienced jet lag from airplane travel across multiple time zones or have suffered the effects of pulling all-nighters at work or in school. We know all too painfully what it means to have a disrupted circadian rhythm.

Put simply, your circadian rhythms depend a lot on your sleep habits. Healthy rhythms help regulate normal hormonal secretion patterns, from those associated with hunger cues to those that relate to stress and cellular recovery. Our chief appetite hormones, leptin and ghrelin, for example, orchestrate the stop and go of our eating patterns. The hunger hormone, ghrelin, tells us we need to eat; the satiety hormone, leptin, says we have had enough. We now have data to demonstrate that inadequate sleep creates an imbalance of both hormones, which in turn adversely affects hunger and appetite. One of the first studies to show the impact of sleep deprivation on eating patterns came from the University of Chicago in 2004.¹⁵⁵ When people slept just four hours a night for two consecutive nights, they experienced a 24 percent increase in hunger and gravitated toward high-calorie treats, salty snacks, and starchy foods. This is probably due to the body’s search for a quick energy fix in the form of carbs, which are all too easy to find in the processed, refined varieties. I also get very hungry, particularly for carbs, when I stay up late writing grant applications.

Dr. Paolo Sassone-Corsi is a professor of biological chemistry and director of the Center for Epigenetics and Metabolism at the University of California–Irvine. Paolo has been studying circadian rhythms for more than twenty years, in particular the relationship between circadian rhythms, timing of eating, and weight control. Calories cannot tell time, but the body can through its circadian rhythms. He has taken genetically identical mice and fed them exactly the same food, but at different times. One group was fed at the normal time for its internal clock, while the other was fed at the wrong time. The normal-time group remained normal, while the other group got fat. One interpretation is that the stress induced by eating food at a time incompatible with one’s metabolic cycles changes how the body handles that food. But see the next section, too.

Paolo has been a key player in our understanding of how hormones are linked with our circadian clock and how proteins involved with circadian rhythms and metabolism are intrinsically linked and co-dependent. For example, the Clock gene produces a protein, CLOCK, that is an essential molecular gear of the circadian machinery. CLOCK interacts with a protein called sirtuin 1 (SIRT1), which senses cell energy levels and regulates metabolism and aging. When these important interactions are disrupted or off balance, normal cellular function can be compromised, leading to illness and disease. This can also be related to sleep patterns and diet, because quality sleep and nutrition may help maintain or rebuild the balance and also explain, at least in part, why sleep deprivation or disruption of normal sleep patterns can increase hunger, leading to obesity-related illnesses and accelerated aging.

In 2015, the National Sleep Foundation, along with a group of experts, issued its new general recommendations for sleep. Babies, for instance, require more sleep than elderly individuals. But bear in mind that the recommendations are mostly generated by averaging how much we slept historically. There are very few studies that can say precisely how much sleep each of us needs. Individual sleep needs will probably be somewhat different, and the most important sleep number to maintain is the right amount of the restorative, slow-wave deep sleep. Although we need just one to two hours of slow-wave sleep per night, we know little about how to induce or facilitate it.

Millions of Americans suffer from sleep disorders, the most common ones being insomnia and sleep apnea. An array of factors can cause insomnia, from medications and medical conditions to alcohol and caffeine consumed too late in the day. While drinking can make you sleepy, it also disrupts restorative, slow-wave sleep. Sleep apnea affects a whopping twenty-two million of us and is caused by a collapse of the airway during sleep; muscles in the back of the throat fail to keep the airway open. This results in frequent cessation of breathing, which causes sleep to be fragmented. Dreamless sleep and loud snoring are telltale signs of sleep apnea. Sleep apnea has a strong relationship with obesity; in fact, the most common cause of sleep apnea is obesity. That extra weight and fat around the neck help to trigger the airway collapse. Although sleep apnea can be treated, usually with the help of a continuous positive airway pressure (CPAP) device, the best solution is weight loss. People who lose weight often find relief and may no longer need a CPAP device.

The fact that shift work has been linked to obesity, heart attack, several types of cancer (breast, prostate), a higher rate of early death, and even lower brainpower has everything to do with the connection between light and our circadian rhythms. People who work night shifts may think they can “train” their bodies to happily be up at night and sleep during the day, but the research tells a different story.

Documenting this association started when two of Dr. Eva Schernhammer’s colleagues developed cancer with no risk factors or a history of the disease. These were healthy women in their thirties. At the time, Schernhammer worked rotating night shifts in a Vienna, Austria, cancer ward from 1992 to 1999, where in addition to her regular hours she had to work through the night ten times a month. When she moved to Harvard Medical School three years later, Schernhammer looked at the available medical, work, and lifestyle records of nearly seventy-nine thousand nurses enrolled in the famous Nurses’ Health Study. Remarkably, she discovered that those who had worked thirty or more years on night shifts had a 36 percent higher rate of breast cancer, compared with those who had worked only day shifts.¹⁵⁶ She continued to investigate further and documented more disturbing findings. By late 2005, she published reports that her fellow female night owls had a 48 percent rise in breast cancer. In comparison, blind women had a 50 percent reduced risk of breast cancer. Multiple studies have since confirmed links between shift work and higher risk of a variety of cancers and cardiovascular and metabolic disease.¹⁵⁷ The causes most often given are the repercussions of a disrupted circadian rhythm and low levels of the sleep-inducing hormone, melatonin. Very recent research has linked these to changes in the epigenome.¹⁵⁸

WHEN WE EAT IS AT LEAST AS IMPORTANT AS WHAT WE EAT

Satchidananda Panda is a professor in the Regulatory Biology Laboratory at the Salk Institute for Biological Studies in La Jolla, California. He has worked extensively on the circadian clock, especially as it relates with our genes, microbiome, eating patterns, risk for weight gain, and even our immune system. One of his most important discoveries showed how light sensors in the eyes work to keep the rest of the body on schedule. The hypothalamus is the part of our brains that links the nervous and endocrine systems—it regulates many of the autonomic functions of our body, particularly metabolism. The suprachiasmatic nuclei in the hypothalamus receive input directly from these light sensors in the retinas of our eyes and serve to “reset” our circadian clock. This is why exposure to early morning light helps reset the circadian clock and explains why getting out into the morning sun can help to recalibrate your clock after a late night or from jet lag.

No doubt you have read in many diet books that it is best to eat small meals throughout the day rather than three larger meals. This is an example of something that seems to make sense (frequent small meals are thought to prevent hunger pangs) but that actual experiments showed to be completely false. Strikingly, Panda and his colleagues found that mice consuming their calories within a set amount of time (twelve hours) were slimmer and healthier than those that ate the same number of calories but over a larger time window.¹⁵⁹ Put another way, the periodic fasting between meals, followed by a longer period of fasting during the sleep period, made mice leaner and healthier than mice that consumed the same number of calories throughout twenty-four hours. But why? We don’t fully understand how a time-based eating pattern can prevent weight gain and illness, but Panda and his colleagues think that the timing of meals influences the circadian clock, which in turn affects the function of genes that are involved with metabolism.

The microbiome also has diurnal cycles that play an important role here. Panda has done extensive work on how the gut bacteria wax and wane throughout the day and how such variations hinge on day and night cues. In one very important study, he and his colleagues compared the microbiomes of mice fed normal food with those given high-fat fare. They measured the composition of the gut microbiome every four hours, rather than taking a snapshot once a day. In the mice on normal diets (that ate during the night and slept during the day), Panda documented dramatic fluctuations in the particular genera of bacteria present at any given time. In the mice that ate a high-fat diet and generally fed around the clock, however, not only did their microbiomes not fluctuate, but these mice gained weight and developed diabetes.¹⁶⁰ These patterns were evident among multiple species of bacteria, including Firmicutes, a type of bacteria that has been associated with obesity and disease in multiple studies around the world. Panda’s group was able to show that it is not necessarily whether an organism has high or low Firmicute levels that dictates health, but when or how often those levels peak. Healthy mice can have high Firmicute levels during the night when they normally eat, but this naturally wanes during the day when they should be sleeping. However, in obese mice, Firmicute levels remain high all the time.

If the thought of timing your meals more precisely throughout your day is starting to stress you out, then I invite you to read on.

STRESS

We all know that chronic, unrelenting stress does not do a body good, and many of us are under unprecedented levels of stress today. According to an American Psychological Association survey, about one-fourth of Americans rate their stress level as 8 or more on a 10-point scale.¹⁶¹ In general, each individual responds to stress a little bit differently. Some of us turn to comfort foods to soothe our anxiety, while others simply cannot eat. When the body is under high levels of acute stress—say, before you have to take an important exam or need to do something you dread—high levels of adrenaline in the body will suppress appetite in the short term. Your brain sends signals to the adrenal glands atop the kidneys to pump out the hormone epinephrine (adrenaline), which shuts down your hunger cues, while your hypothalamus produces corticotropin-releasing hormone to increase secretion of the stress hormone, cortisol, thereby preparing the body to recover from stress. This primes you to engage in a fight-or-flight response to the stress and then to recover from it.

But what happens when stress becomes chronic, when it does not disappear? Austro-Hungarian endocrinologist Hans Selye is generally credited with coining the term “stress,” or “general adaptation syndrome.”¹⁶² Selye observed that chronic stresses of different kinds induced more or less the same response, swelling of the adrenal cortex, increased liver weight, atrophy of the thymus, and ulcers. He recognized that this was a pathological response to the constant presence of a stressor. This type of stress, such as dealing with everyday demands at work and home, provokes a different response in the body that can include what some call “emotional eating”—overeating indulgent (sugary, fatty) foods. The stress hormone, cortisol, is intended to increase appetite and stimulate recovery from acute stress. The combination of high cortisol, high insulin due to food intake, and high motivation to eat is a recipe for weight gain and obesity. Cortisol not only tinkers with hunger cues, it tells your body to store more fat and break down tissues that can be used for quick forms of energy, including muscle. Prolonged high levels of cortisol can lead to increased abdominal fat (particularly that nasty, visceral kind), mood disorders (such as depression), bone loss, a suppressed immune system, fatigue, and an increased risk for insulin resistance, diabetes, and heart disease.

It is important to note that the brain’s reward system, which regulates our ability to feel pleasure, is also at play. The addiction literature has long documented how the reward system is impacted by drugs such as nicotine, cocaine, and heroin—powerful substances that target the pleasure center and keep addicts coming back for more. This same literature now suggests that this reward circuitry may have a central role in stress-induced food intake. So similar to drug addicts, who were once labeled as people who lacked self-control, food addicts can partly blame their “lack of control” on how their brain is speaking to them and creating impulses to eat. Did you ever see the “Betcha can’t eat just one” commercial? Stress, together with highly palatable food, can stimulate the release of “intoxicating,” feel-good brain chemicals—natural opioids, in fact—that keep one coming back for more.¹⁶³ The release of these opioids may actually be part of our bodily defense mechanism against the stress response, helping us to turn its volume down. But repeated stimulation of the reward pathways through the stress response, coupled with an intake of highly tasty food, can lead to neurobiological adaptations that contribute to the compulsive nature of overeating.¹⁶⁴^,¹⁶⁵

Overeating is not the only stress-related behavior linked to weight gain. Stress makes you less likely to exercise, more likely to turn to comfort foods or to substances such as alcohol, and more likely to have trouble sleeping—all of which further contribute to excess poundage.

PHARMACEUTICALS

A variety of prescription drugs we take have the unpleasant side effect of causing weight gain. If you use any pharmaceuticals on a regular basis, read the fine print in their packaging to see whether “weight gain” or “changes in appetite or weight” are listed as side effects. (RxList and WebMD are good online sites to check for information.) This is not to say you should immediately discontinue their use, but raise the issue with your doctor. You should always be made aware of the expected benefits as well as potential risks of any medical intervention, particularly prescription drugs.

The fact certain drugs can cause weight gain is perhaps the strongest proof that chemical obesogens exist and can cause obesity in humans. Drugs are merely chemicals tested for effectiveness against a particular condition. Many of these drugs target the same physiological pathways as chemical obesogens (for example, tributyltin and the diabetes drug rosiglitazone, aka Avandia). Some medications can make you feel hungrier, while others slow your ability to burn calories or cause you to hold on to extra fluids. However, not everyone responds equally to the same drugs. You might not gain an extra pound while taking a certain drug, while your friend puts on fifteen pounds on the same medication. Again, this is evidence as to the individuality of human biology. Many factors come into play, from underlying genetics and epigenetic programming to environmental impacts and exposures. Let’s take a quick tour of the most common pharmaceutical obesogens.

Depression medications (for example, Celexa, Prozac, Paxil, Zoloft): The so-called SSRIs (selective serotonin reuptake inhibitors) as well as “tricyclic antidepressants” have a long history of being associated with weight gain.¹⁶⁶ The tricyclic drug amitriptyline (Elavil) in particular has been shown to induce sugar cravings and considerable weight gain in some people.¹⁶⁷ Keep in mind that depression itself can affect your appetite and eating habits as well. Note that some of these medicines, such as Elavil and Pamelor, are also used to treat seizures and migraines.

Mood stabilizers (such as Clozaril, Seroquel, Risperdal): These drugs help treat mental health conditions such as bipolar disorder or schizophrenia. Through their effects on the brain, they affect your weight and metabolism by keeping your appetite turned on. Some may cause as much as an eleven-pound weight gain in ten weeks. People taking them for a long time may gain more. The antipsychotic drug olanzapine (Zyprexa) in particular has been shown to induce considerable weight gain and obesity.¹⁶⁸^,¹⁶⁹

Diabetes drugs (for instance, Diabinese, Insulase, Actos, Avandia): These drugs control blood sugar levels, but do so in different ways. Some make you more sensitive to insulin, while others trigger the body to release more insulin before or after meals. Weight gain is normal when starting these drugs, for the body takes time to adjust. But older generations of these drugs such as Actos and Avandia can lead to substantial increases in body fat content.¹⁷⁰ People with type 2 diabetes who are already overweight find the extra weight particularly frustrating.

Corticosteroids (such as Medrol, prednisone): Corticosteroids reduce pain and inflammation and are not the same as the anabolic steroids often abused by bodybuilders and athletes. Corticosteroids have long been known to trigger appetite and foster fat storage in humans.¹⁷¹ They are often prescribed to treat an array of different conditions, such as severe allergies or skin problems, asthma, arthritis, or Crohn’s disease.

Over-the-counter allergy medications (for instance, Zyrtec, Benadryl, Allegra, Claritin): Over-the-counter allergy meds block the action of histamine, a chemical your body makes that causes many of the symptoms of allergies. A 2010 study published in the journal Obesity reported an association between the use of antihistamines and obesity. The study found that of nearly nine hundred people studied, those taking antihistamines were more likely to be overweight or obese than those not taking these drugs.¹⁷² The underlying reasons for this were not clear, and this association does not prove that the antihistamines caused obesity. The researchers speculated that antihistamines have similar chemical structures to certain psychiatric drugs that are known to be associated with weight gain, as they may increase appetite.

VIRUSES

Interestingly, evidence is accumulating that exposure to some viruses, such as the adeno-associated virus 36, may influence risk for becoming overweight or obese. In the past several years, a number of studies in humans have shown that infection with adenovirus 36, a virus that causes upper-respiratory infections, leads to fat weight gain, especially in children.¹⁷³ These studies support earlier research that showed the virus causes weight gain in mice, rats, chickens, and monkeys. How this happens is similar to how some chemical obesogens work: by prompting adult stem cells in fat tissue to make more fat cells, which then store more fat. When researchers examined the fat pads from infected animals and compared these with those of uninfected animals, they noted that the infected animals had bigger fat cells and more of them. When they infected human adult mesenchymal stem cells in tissue culture, the cells differentiated into fat cells—without even adding differentiation agents to the culture. In 2013, a team of researchers at Pennington Biomedical Research Center at Louisiana State University published a study that followed fourteen hundred people, finding that those who tested positive for antibodies to the virus—indicating that they had been infected at some point—gained significantly more weight in the form of body fat over a ten-year period than those who had not been infected.¹⁷⁴

Counterintuitively, despite its effects on obesity, exposure to this virus seems to improve other metabolic parameters, notably lowering cholesterol and triglycerides and improving blood sugar control. But the researchers studying this virus do not yet know why and are currently searching for ways to manipulate the virus to promote such positive outcomes while minimizing the fat-inducing effects. In addition, not every obese individual has these exposures, and not all of those who have been exposed are overweight or obese.

FAT GENES

I would be remiss to leave genetics out of this discussion. Are some people saddled with “bad genes” that make them more susceptible to weight gain and sensitive to chemical exposures? The answer is yes, but not so many. That is, there are genes that have been associated with obesity, but the existence of such genes cannot come close to explaining the magnitude of the obesity epidemic, as we discussed already. The most recent, large-scale meta-analysis of genes that might be associated with obesity identified ninety-seven regions of the genome that were associated with variations in BMI. This analysis included 339,224 individuals from 125 previous studies and concluded that these ninety-seven regions could account for about 2.7 percent of the variation in BMI among individuals—a very small amount indeed.²⁵

Some of the genes identified were linked with the central nervous system (that is, the regulation of eating and metabolism), whereas others were associated with expected factors such as insulin signaling, the development of fat cells, the regulation of fat import/export into fat cells, and overall energy metabolism. The researchers proposed that these results indicated that as much as 20 percent of variability in BMI might be explained genetically—still a very small number. The bottom line is that genetics does play a role in susceptibility to obesity, but that probably 80 percent or more of obesity has causes other than mutations in genes that have been, or can be, identified. This is not so different from the overall association between genes and diseases of about 20 percent.

CHAPTER 5

It Gets Complicated

Other Fat-Inducing Factors